DE2628469A1 - Gamma-amino alcohols prepn. - from beta-dicarbonyl cpds., and their conversion into azetidine derivs. - Google Patents

Abstract

In a novel prodn. of gamma-amino-alcohols, a beta-dicarbonyl cpd. of the formula R1-CO-CR2R3-CO-R4 (I) or R1-CO-CR2R3-CO-OR5 (II) (where R1 is H, alkyl, aryl, or alkylaryl; R2 and R3 are H, alkyl, aryl, alkylaryl or a heteroaromatic or alkylheteroaromatic residue; R4 is H, alkyl, aryl or alkylaryl; and R5 is alkyl) is reacted with an alkoxyamine to give a monoalkoximino intermediate. The intermediate is reduced to the gamma-amino-alcohol. The gamma-amino-alcohol products are cpds. of the formula H2N-CHR1-CR2R3-CHR4-OH (III). Such cpds. in which R2 and R3 are each H, alkyl, aryl, alkylaryl or a heteroaromatic residue and at least one of R2 and R3 is a heteroaromatic residue are claimed as new cpds. Aminoalcohols of formula (III) are useful as intermediates for azetidines, the prodn. of which is claimed. The azetidine derivs, are useful as pesticides active against e.g. spider mites. They are active against both adult and nymph forms of such pests. In an example, ethyl 3-amino-3-(3-pyridyl)propionate is reacted with tosyl chloride, the resulting N-tosyl cpd. is reduced with LiAlH4, the resulting 3-(p-toluenesulphonamido)-3-(3-pyridyl)propanol is reacted with tosyl chloride, and the resulting 3-(p-toluenesulphonamido)-3-(3-pyridyl)-propyl p-toluenesulphonate is cylised to give 2-(3-pyridyl)-N-(p-toluenesulphonyl)-azetidine.

Description

γ-Amino alcohols and processes for their preparation There are numerous Azetidine compounds are known with a wide range of applications. One of the possible uses these compounds are based on the relationship between azetidine and ethyleneimine. The alkylation effect of both compounds as well as the effectiveness of ethyleneimine in various therapeutic areas has led to intensive research on azetidine analogs of ethyleneimine derivatives with known clinical suitability for combating neoplastic Diseases led.

Azetidine derivatives have also been used with success in the known Vilsmeier-Haack reaction used. In this case it is azetidinamides.

The aforementioned and other investigations were, however, carried out the small number of azetidine compounds available hitherto severely hindered. This Bottleneck, in turn, depends on the conventional methods of making these connections which allow the synthesis of only a relatively small number of azetidine compounds.

A conventional synthetic method for azetidine compounds exists in the reaction of amino esters with a Grignard reagent, resulting in ring closure Azetidinones (B-lactams) form, which are then combined with lithium aluminine hydride to form Azetidine derivative can be reduced. However, this implementation can only be perform successfully on amino esters with a limited number of substituents. It is therefore unsuitable for the production of numerous desired compounds proven.

Other methods of making azetidine compounds - such as those which Vaughan et al. in Journal of Organic Chemistry 26 (1961), page 138, and is based on γ-amino alcohols - are also restrictions subject. In these cases too, there are few suitable starting materials available.

γ-Amino alcohols have so far been made in stages by converting ammonia or amines with substituted acrylic acids or esters to the corresponding β-amino acid (or to the corresponding ester) and reduction of the B-amino acid.

Such a step synthesis has considerable disadvantages. the The first stage reaction with ammonia or an amine is common complicated by competing side reactions such as amide formation. Further this synthesis (especially the final reduction stage ) severely impaired by the presence of substituents on the intermediates. Therefore, many of the desired compounds have hitherto been very small and difficult isolable amounts available while other compounds are not generated at all could become.

There has long been a need for an alternative method of synthesis of γ-amino alcohols. Furthermore, a method for the preparation of γ-amino alcohols having substituents is disclosed aimed in a-, ß- and / or y-position.

The invention thus relates to a new method for the production of Azetidine compounds and certain related novel precursors or connections.

In particular, the invention relates to the preparation of valuable azetidine compounds, like new 2-substituted and 3-substituted azetidine derivatives.

Some azetidine compounds of the present invention are made from β-amino esters of the general formula below in which R1 and R2 each represent a hydrogen atom or an alkyl, aryl, aralkyl, heteroatomatic or alkylheteroaromatic radical, R3 and. R4 each represents a hydrogen atom, an alkyl,. Aryl, aralkyl, heteroaromatic or alkylheteroaromatic radical and R5 is an alkyl radical, usually a methyl or ethyl group, is prepared.

In the context of the invention, “alkyl radicals” are alkyl radicals with 1 up to 10 carbon atoms, preferably 1 or 2 carbon atoms. The term '' Arylreste'l refers to aromatic residues such as the phenyl, Tolyl, chlorophenyl or naphthyl group. Among aralkyl radicals are radicals of the type the benzyl group, under "heteroaromatic radicals" radicals such as the pyridyl or furanyl group and under 11alkylheteroaromatic radicals "the radicals analogous to the aralkyl radicals, like the picolyl group.

Aromatic ring structures can also have substituents. at the substituents can be, for example, alkyl, cycloalkyl, aryl, aralkyl, heteroaromatic or alkyl heteroaromatic radicals or halogen atoms act, which are on a any available ring carbon atom. In the case of heteroaromatic or alkyl heteroaromatic radicals (or compounds) are also the acid addition salts, like the hydrochloride.

The scope of the invention is made possible by the presence of substituents not exceeded on the amino ester. These substituents can, however, to a certain extent Slow down the reactions resulting from the azetidine derivatives. Therefore is at a particularly preferred embodiment of the invention at least one of the Radicals R3 and 24 represent a hydrogen atom. In an even more preferred embodiment one of the radicals R1 and R2 is also a hydrogen atom, while the other is this Represents radicals a pyridyl or substituted pyridyl group.

Many β-amino esters are readily available, but often they are only in the form of the salts, since the amino esters themselves are not stable over a long period of time. If the desired starting material is therefore in the form of a salt (such as the hydrochloride) received, one should neutralize this first. The neutralization can be carried out in a conventional manner Manner, for example with the help of an aqueous sodium carbonate solution.

Optionally, suitable β-amino esters can be selected from the corresponding ones available Aldehydes, acids or alcohols are produced. For example, you can use the Aldehyde in the Castle et al. in J. Am. Pharm. Assoc., 43 (1954), 163, Transferring the described manner into the acid and then esterifying it. As well you can get the ester from a corresponding alcohol by oxidation and subsequent Produce esterification of the acid obtained.

To bring the amino esters into a form from which they form the azetidine ring structure can be cyclized, you must first both the ester and the amino group convert it into a reactive form. One can do this by sulfonating the two groups Achieve, on the one hand a sulfonamide and on the other hand a sulfonate group develop. Reagents suitable for sulfonation have a remainder of the general Formula -S02R, where R is an alkyl, aryl or aralkyl radical.

Said radical is preferably a tosyl group, in particular a p-tosyl group. Examples of reagents that can be used to activate the amino ester are the toluenesulfonyl halides, such as p-tosyl chloride or p-tosyl bromide.

It has been found that the amino esters according to the invention, in particular the β-substituted amino esters, not directly into the cyclizable Shape are convertible. Rather, a three-stage reaction sequence is required for this.

The sulfonamide is formed in the first stage. This is done for example by reacting tosyl chloride with the amino ester. The reaction is said to be in the presence a suitable solvent, preferably a weakly basic organic one Connection, such as that of pyridine.

The sulfonamidoesters are for a period of at least about 1 to 2 hours at temperatures from 250C to the freezing point of the solvent, preferably from -10 to + 10 ° C.

The respective sulfonamidoester then becomes the corresponding one Sulfonamido alcohol reduced. This procedural stage can be carried out with the help of any conventional strong reducing agent. Examples of suitable Reducing agents are mixed metal hydrides such as LiAlH4 or NaAlH2- (OCH2CH20CH52.

The reduced sulfonamido alcohol can then with further tosyl chloride or the like. Reacted to the 3-sulfonamidoalkyl sulfonate. The response should be in be carried out in the manner described for the formation of the sulfonamidoester, although in this case up to about 24 hours

may be required.

The ring is closed by splitting off the sulfonate group from the sulfonamidonyl sulfonate. This cleavage and the resulting cyclization can be carried out by conventional methods take place. Examples of this are those of Vaughan et al. in Journal of Organic Chemistry, 26 (1961), page 138, described procedures. Preferably the cleavage and the ring closure, however, with the aid of potassium tert-butoxide dissolved in tert-butanol performed. Through the ring closure one obtains the N-sulfonylazetidine, preferably p-doluenesulfonylazetidine.

Azetidine compounds according to the invention are also obtained from γ-amino alcohols of the general formula below in which R1 and R2 each represent a hydrogen atom or an alkyl, aryl, aralkyl, heteroaromatic or alkylheteroaromatic radical and R3 and R4 each represent a hydrogen atom or an alkyl, aryl or aralkyl radical.

“Alkyl radicals” in turn includes alkyl radicals having 1 to 10 carbon Atoms, preferably 1 or 2 carbon atoms to understand. Furthermore mean: “Aryl radicals” aromatic radicals such as the phenyl, tolyl, chlorophenyl or naphthyl group; "Aralkyl" radicals of the benzyl type; 1, heteroaromatic residues "residues such as the pyridyl or furanyl group; and "" alkyl heteroaromatic radicals "den Alkylaromatic radicals are analogous to radicals, such as the picolyl group.

Aromatic ring structures can also have substituents. at the substituents can be, for example, alkyl, cycloalkyl, aryl, aralkyl, heteroaromatic or alkyl heteroaromatic radicals or halogen atoms act, which are on a any available ring carbon atom. In the case of heteroaromatic or alkyl heteroaromatic radicals (or compounds) are also the acid addition salts, like the hydrochloride.

The scope of the invention is made possible by the presence of substituents not exceeded on the y-amino alcohol. However, these substituents can lead to a lead to a certain slowing down of the reactions resulting from the azetidine derivatives. Therefore is at least in a particularly preferred embodiment according to the invention one of the radicals R3 and R4 is a hydrogen atom. With an even more preferred one Embodiment is also one of the radicals R1 and R2 is a hydrogen atom, while the other of these radicals represents a pyridyl or substituted pyridyl group.

Γ-amino alcohols which can be used according to the invention are commercially available. These amino alcohols or their derivatives, which fall under the aforementioned general Formula falling can be used as starting materials in the process of the invention will.

In the process according to the invention, starting materials can also be used, which represent new connections. These are in particular the γ-amino alcohols with α, β or γ substituents, in particular with a β-pyridyl or substituted one β-pyridyl group. Corresponding new ones can be obtained from these new starting compounds Azetidine derivatives such as 3-substituted azetidines can be prepared.

The invention thus also relates to the production of these γ-amino alcohols for a new synthetic route. In particular, it was found that B-dicarbonyl compounds, such as ß-diketones, ß-eetoesters and a-formyl derivatives of esters, ketones and aldehydes, into the corresponding γ-amino alcohols and, if required, then into azetidine derivatives can be transferred.

Suitable starting materials for the synthesis of the γ-amino alcohols are the compounds of the general formulas A or B: in which R1 is a hydrogen atom or an alkyl, aryl, aralkyl or alkylaryl radical, R2 and R3 are each a hydrogen atom or an alkyl, aryl, aralkyl, alkylaryl, heteroaromatic or alkylheteroaromatic radical, R4 is a hydrogen atom or a Denotes alkyl, aryl, aralkyl or alkylaryl radical and R5 denotes an alkyl radical.

"Alkyl radicals" are again alkyl radicals with 1 to 10 carbon atoms, preferably the methyl or ethyl group. Furthermore: 'BAryl residues' mean aromatic radicals such as the phenyl, tolyl, chlorophenyl or naphthyl group; "Aralkyl radicals" Residues of the benzyl group type; heteroaromatic residues such as the pyridyl or furanyl group; and "" alkyl heteroaromatic radicals "denote the alkyl aromatic radicals Residues analogous residues such as the picolyl group.

Aromatic ring structures can also have substituents. at the substituents can be, for example, alkyl, cycloalkyl, aryl, aralkyl, heteroaromatic or alkyl heteroaromatic radicals or halogen atoms act, which are on a any available ring carbon atom. In the case of heteroaromatic or more alkyl heteroaromatic Remnants (or compounds) are also the acid addition salts, like the hydrochlorides, are also included.

According to this embodiment of the invention, the β-dicarbony starting compound with an alkoxyamine) preferably methoxyamine, ethoxyamine or benzyloxyamine, for corresponding ß-alkoximino derivative. The reaction is quick and will usually in the presence of a suitable solvent (such as methanol) at room temperature or made above. The alkoxyamine and the ß-dicarbonyl compound are said to be in are usually used in practically equimolar proportions. Favored by this one the formation of the monoalkoximino intermediate.

The formation of the monoalkoximino intermediate occurs generally takes place without difficulty. The reaction with the alkoxyamine on one of the two carbonyl groups of the molecule is usually selective. Accordingly, one normally achieves one Yield of at least about 80%. If one of the carbonyl groups is part of a Is an ester group, the alkoximino formation takes place exclusively on the other carbonyl group. There can thus be a practically quantitative conversion to the monoalkoximino intermediate take place.

After the monoalkoximino derivative has been formed, it is reduced to a γ-amino alcohol according to the invention. The reduction can be done with the help of almost one any strong reducing agent can be performed. Particularly preferred reducing agents however, are the mixed metal hydrides.

For example, you can use LiAlH4, NaAlH2- (OCH2CH20CH3) 2 or something similar Use reducing agent.

As is usual with such a reduction, the implementation should in the presence of a suitable solvent, such as dimethoxyethane. If susceptible substituents, such as heteroaromatic radicals, are present, leads one the Implementation preferably at low temperature. Thus, temperatures of less than about 200 ° C., in particular of about -10 to + 5 ° C. Usually at least 3 to 5 days are allowed for the reaction to complete necessary. If only stable substituents, such as alkyl or aryl radicals, are present however, the use of higher temperatures (up to about 10,000) is permissible. Such temperatures increase the reaction time (up to 1 to 2 hours) shortened.

After the reduction, the γ-amino alcohol can be isolated.

For this purpose, the reaction mixture is usually dispersed in an immiscible aqueous-organic solvent system. Then will separated the organic phase. When the solvent is distilled off, one obtains the product, i.e. the γ-amino alcohol.

Certain compounds made in accordance with the present invention belong to the state of the art of the technique. For example, many such compounds have known pharmacological ones Effects. These compounds and their uses are described in US Pat. No. 2,151,517, in JA-PS 14 788 (1963) and in "Irremor-Producing Aminopropanols't, Horner et al., Journal of Medicinal Chemistry, 10: 387-391 (1967).

In contrast, various compounds produced according to the invention are new. These are the amino alcohols of the following general formula: in which R1 is a hydrogen atom or an alkyl-1 aryl, aralkyl or alkylaryl radical, R2 and R3 are each hydrogen or an alkyl, aryl, aralkyl, alkylaryl, heteroaromatic or alkylheteroaromatic radical, R4 is a hydrogen atom or a Alkyl, aryl, aralkyl. or alkylaryl radical and at least one of the radicals R2 and R3 represents a heteroaromatic or alkylheteroaromatic radical.

Particularly preferred new compounds are those which, as a-, B- and / or y-substituents have alkyl radicals with 1 to 5 carbon atoms. Analogue are preferred aryl and alkylaryl or. Aralkyl radicals, the phenyl and tolyl groups or the benzyl group, whereas of the heteroaromatic radicals the pyridyl and Furanyl group and, of the alkyl heteroaromatic radicals, the picolyl group is preferred will. In these new compounds, at least one of the radicals R2 and R3 must be heteroaromatic radical, preferably one in which the hetero atom is Represents nitrogen atom.

Most preferred are the compounds of the general above Formula in which one of the radicals R2 or R3 represents a pyridyl group.

These aromatic radicals can be bound to the amino alcohol or are in any ring position. In the case of the pyridyl group however, the 3-pyridyl group is prevented. The aryl, aralkyl, alkylaryl, heteroaromatic and alkylheteroaromatic radicals have different ring substituents as defined above. For example, the available ring valences by hydrogen or halogen atoms or by alkyl, aryl, aralkyl, alkylaryl, heteroaromatic or alkyl heteroaromatic radicals are saturated. Also the acid addition salts e.g. the heteroaromatic and alkylheteroaromatic radicals (or compounds) are included.

As mentioned, many γ-amino alcohols with α, β or γ substituents can be used cannot be produced by conventional synthesis methods. The inventive Reaction sequence makes it possible for the first time that these y-amino alcohol derivatives for the Synthesis of the appropriately substituted ß-dicarbonyl derivatives become available. These new compounds can generally be used for the same purposes as already explained with regard to the conventional γ-amino alcohols. However, they are of particular value for the synthesis of azetidine derivatives.

In order to convert an amino alcohol into the form from which it is under Formation of the azetidine ring structure can be cyclized, one must first both the Convert alcohol and amino groups into a reactive form. One can do this achieve by sulfonation of the two groups, on the one hand the sulfonamide and on the other hand the sulfonate arise.

Suitable sulfonating agents have a residue of the general Formula -S02R, where R can be an alkyl, aryl or aralkyl radical. The most the preferred radical is the tosyl group, in particular the p-tosyl group. examples for Compounds that can be used to activate the amino alcohol are the toluenesulfonyl halides, such as p-2osyl chloride or p-tosyl bromide.

The aforementioned activation can be achieved by direct conversion of the amino alcohol with a suitable reagent such as dosyl chloride. Usually one leads the reaction using a sulfonating agent / amino alcohol molar ratio of about 2: 1 through. The reaction should be carried out in the presence of a suitable solvent, preferably a weakly basic organic solvent (such as pyridine) The 5-sulfonamidoalkyl sulfonates form over a period of 1 to 4 days at temperatures from 250C to the freezing point of the solvent, preferably from -10 to iOOC.

The ring closure is again achieved by splitting off the sulfonate group reached by the sulfonamidoalkylsulfonate. This cleavage and the resulting cyclization can be done in the same way as for the synthesis of azetidine derivatives from aminoesters.

The N-sulfonylazetidines obtained by the ring closure, which corresponding Have substituents, as described above for the starting compounds (γ-amino alcohols or B-amino esters) can then be unsubstituted on the nitrogen Azetidine derivatives are reduced. Any suitable reducing agent can be used use for the conversion of N-sulfonylazetidine; However, sodium naphthalinide will preferred. It is also advisable to use a proton donor to facilitate the conversion, such as tert-butanol to be used. By combining a suitable reducing agent with a proton donator one thus achieves a considerably increased yield of the azetidine derivative unsubstituted on nitrogen. In this case, too, it is advisable to to work at low temperatures; Reaction temperatures from -70 to 4000 C are preferred. The implementation is almost instantaneous.

According to a further embodiment, the aforementioned azetidine alkylated to the N-alkyl azetidine. The N-alkyl azetidines have a similar applicability and can easily be made by conventional methods. One obtains, for example N-methylazetidine derivatives in good yield by reacting the unsubstituted on the nitrogen Azetidins with formaldehyde and formic acid in an aqueous medium.

The azetidine compounds and substituted azetidines of the present invention can, as mentioned, be used for numerous purposes. In this context are also the U.S. Patents 3,076,799 and 3,124,569 and the Belgian patent 624 575 to acquire. Go from these references various special purposes for which the mentioned valuable compounds were used.

In addition to the aforementioned amino alcohols, certain azetidine derivatives according to the invention are also new and cannot be prepared by other known methods. These compounds include the 2-substituted and 3-substituted (especially the pyridyl-substituted) azetidines and their derivatives. These new compounds have the following general formulas: in which R2, R3 and R4 each have the meaning given above with regard to the amino alcohol or amino ester precursors and R6 is a hydrogen atom or an alkyl radical, preferably.

represents a hydrogen atom or a methyl group.

As can be seen from the formulas above, the place of the link is between the pyridyl and azetidine group is not decisive. However, it is preferred the 3-pyridyl group.

The pyridyl group can also have substituents. Any of the four available valences can be replaced by a hydrogen - or Halogen atom or an alkyl, aryl-1-alkylaryl, cycloalkyl, heteroaromatic or alkyl heteroaromatic radical be saturated. That is also included Acid addition salts (such as the hydrochloride) with the (optionally substituted) Pyridyl group.

The aforementioned new compounds are useful for similar purposes like the azetidines in general and as already mentioned. It was, however found that these compounds are also useful as pesticides. As such they can - usually in a form dissolved in a suitable solvent, e.g. as a lying aqueous solution - on plants infested with pests such as spider mites be applied. The compounds mentioned have been found to be common not only against the full-blown forms of these pests, but also against whose nymphs worked.

The following examples are intended to explain the invention in more detail. but without restricting them.

Example 1 A suspension of 114 g (0.69 mol) of β-amino-β- (3-pyridyl) propionic acid in 2850 ml of ethanol is stirred at 50C with a solution of 417 g of sulfuric acid added in 240 ml of ethanol. The batch is stirred for 1 hour, after which the resulting clear solution for 48 hours at room temperature and then below 500C im The vacuum is reduced until the onset of crystallization. Then one carries the solution in a suspension of 715 g of sodium bicarbonate in 1430 ml of water within 1 hour a. The solution is kept at a temperature of about 0 to 5 ° C. After further Stirring for 30 minutes is added 300 ml of carbon tetrachloride and the mixture is stirred Mix for another 10 minutes. The salt formed as a by-product is filtered off and the watery Layer extracted thoroughly with carbon tetrachloride. The combined organic extracts are dried and evaporated in vacuo. 87.11 g (65% yield) of crude ethyl β-amino-β- (3-pyridyl) propionate are obtained in the form of a slightly viscous green liquid.

A solution of 71 g (0.366 mol) of the propionate in 710 ml of pyridine is cooled to -100C and treated with 84 g (0.44 mol) of tosyl chloride. One lets Stand the batch in an ice bath for 2 hours and then at room temperature overnight.

The solution is then poured onto ice and diluted with 3 liters.

Water. The solid product is isolated, washed out with water and dried over potassium hydroxide. 90 g (yield 70%) of ethyl-ß- (p-toluenesulfonamido are obtained ) -β- (3-pyridyl) propionate.

89t7 g (0.26 mol) of the sulfonamide are in a suspension of 12.7 g (0.34 mol) of lithium aluminum tetrahydride in 1250 ml of anhydrous ethylene glycol dimethyl ether (Glyme) entered. The mixture is boiled for 90 minutes with stirring and reflux then add saturated sodium chloride solution at a temperature of 0 to 50C and the mixture boils for a further 30 min. with stirring and reflux. Then you let him The batch stand overnight, the insoluble components are filtered off and the filter cake is washed with 200 ml of boiling ethylene glycol dimethyl ether and then twice with each 250 ml of ethanol. The pH is adjusted to 7.8 with sodium bicarbonate and HCl. Most of the ethylene glycol dimethyl ether and ethanol are evaporated at a reduced rate Pressure is removed, the separated solid is isolated, washed out with water and dried him in the desiccator.

75.6 g (yield 95.5%) of 3- (p-toluenesulfonamido) -3- (3-pyridyl) propanol are obtained.

A solution of 70.5 g (0.23 mol) of the propanol derivative in 750 ml of pyridine is cooled to -50C. Then the solution is gradually added 55 g (0.29 mol) of tosyl chloride, the temperature being kept below 50C. Thereafter the solution is kept at 40C for 24 hours and then with 4 liters of ice and water diluted to a content of 24.4 g (0.29 mol) sodium bicarbonate. The resulting crystalline Solid is isolated, washed out with water and a small amount of ethanol and dried. 90.5 g (yield 86) of 3- (p-doluenesulfonamido) -5-t3-pyridyl) propyl-p-toluenesulfonate are obtained.

2.88 g (0.074 mol) of pure potassium metal are then poured into 2.7 Ltr.

registered anhydrous tert-butanol. The mixture is boiled for 90 minutes. (until the metal has dissolved) with stirring and reflux. After setting the At a temperature of 30 ° C., 30 g (65 mol) of the sulfonate are added and the solution is boiled 10 hours with stirring and reflux. The solution is then filtered while hot and washes the filter cake with boiling methylene dichloride. About the washing water The combined filtrate is evaporated to dryness under reduced pressure. Included 2.6 g of solid crude product are obtained. This is redissolved in methylene dichloride and filtered again. 1) Replace the methylene dichloride with boiling one Ethyl acetate, the mixture is concentrated to 110 ml and left to stand overnight. the shiny, dense, colorless prisms of pyridyl) -p-toluenesulfonylazetidine formed in the process are isolated. 17.16 g (92% yield) of the azetidine are thus obtained. When constricting of the filtrate to 10 ml, a second crop of crystals is obtained.

Analysis for C15HlóN2SO2 0 H N S calc .: 62.47 5.59 9.71 egg, 12% found: 62.66 5.80 9.90 11.11% Example 2 A solution of sodium naphthalenide is prepared in 2 ltr.

anhydrous ethylene glycol dimethyl ether from 38.4 g (0.3 mol) of naphthalene and 5.75 g (0.25 mole) sodium metal. This solution turns into a solution of 18.4 g (64 mmol) of the azetidine from Example 1 in 4.72 g (64 mmol) of tert-butanol and 1 Ltr. Ethylene glycol dimethyl ether registered.

1750 ml of the sodium naphthalinide solution are added within 2 hours. added, the temperature of the reaction medium in the range from -60 to -650C. 60 ml of methanol are then added and the reaction mixture is heated to room temperature and let it stand overnight.

The solution is then filtered and the filtrate is concentrated under reduced pressure Pressure is strong, the residue is taken up in petroleum ether and filtered again. The clear, discolored petroleum ether filtrate is extracted five times with 20 ml each time Water and concentrated the combined aqueous extracts under reduced pressure to 20 ml of a naphthalene-free solution of the crude product. This solution dehydrates one by azeotropic distillation using benzene and ethanol. Included a benzene solution of the product is obtained, which after removal of the solvent is distilled in vacuo. Distillation gives a fraction of clear, colorless 2- (3-pyridyl) azetidine (2.87 g or

33.6% yield). The product boils at 73 to 750C / 0.05 mm; IR (undiluted) 3225 (s), 800 (m), 713 cm (s); NMR (CDCl3) cF 1.50 to 2.70 (m, 3) (became 2H, with D20), 3.28 to 3.70, (m, 2) 4.87 (t, J = 7H2.1), 7.15 (m, 1), 7.72 (m, 1), 7, 72 (m, 1), 7.72 (m, 1), 8.4 to 8.55 (m, 2); Mass spectrum mte (relative intensity) 134 (23, M +), 133 (31), 105 (100).

Analysis for C8H10N 2: C H N calc .: 71.61 7.51 20.88% found: 71.69 7.76 21.01% Example 3 A solution of 920 mg (6.88 mmol) of the according to Example 2 prepared 2- (3-pyridyl) -azetidins in 9 ml of water is with a solution of 660 mg (8.83 mmol) of 40% strength by weight (w / w) formaldehyde in 9 ml of water and 755 mg (14.5 mmol) of 88% formic acid in 9 ml of water are added. One heats the Approach 2 hours on the steam bath, then cools it down to OOC, adds 1.21 g (14.4 mmol) Sodium bicarbonate is added and the colored solution is concentrated under reduced pressure 7 ml a.

The solution is then dehydrated by azeotropic distillation using benzene and ethanol, taking an insoluble component containing anhydrous benzene solution is obtained. The insoluble components are filtered off; the filtrate is a solution of N-methyl-2- (3-pyridyl) azetidine.

Short-path vacuum distillation gives 400 mg of N-methyl-2- (5-pyridyl) azetidine in the first fraction from bp 49 to 50 ° C; 0.025 mm; IR (neat) 3225 (s), 800 (m), 713 cm (s); NMR (CDC13) cr 1.9 to 2.5 (m, 2), 2.3 (s, 3, CH3), 2.9 to 3.4 (m, 2), 3.9 (m, 1), 7.25 (m, 1), 7.78 (m, 1), 8.3 to 8.6 (m, 2); Mass spectrum m / e (relative intensity) 148 (25, M + 147 (28), 119 (100).

Analysis for C9H12N2: C H N calc .: 72.94 8.16 18.90% found: 72.85 8.07 18.73% Example 4 36.8 g of sodium bicarbonate are mixed with 36.2 g of methoxyamine hydrochloride Stirred in 1.5 liters of methanol until the evolution of gas has ceased. Then you cool down the mixture is reduced to 50 ° C. and 81.8 g of ethyl 2-formyl-2- (3-pyridyl) acetate are added. The mixture is then stirred for 12 hours at room temperature and concentrated under reduced pressure High pressure and distribute the residue between water and methylene dichloride. The organic phase is saturated with saturated sodium bicarbonate solution, water and Washed sodium chloride solution. 74 g (78.5%) of ethyl 2- (3-pyridyl) -3-methoximinopropionate are obtained by distillation from bp 114 to 116 ° C / 0> 15 mm.

22.65 g of the ethyl 2- (3-pyridyl) -3-methoximinopropionate are obtained within 2 1/2 hours into a slurry of 17.45 g of lithium aluminum hydride in 1 line of dimethoxyethane registered. The temperature is kept at -5 to OOC. After standing for 5 days at room temperature the mixture is cooled to Ooc and gradually washed with 85 ml of saturated sodium chloride solution offset. After 4 hours the mixture is filtered and evaporated under reduced pressure a.

The oily residue is by azeotropic distillation with benzene and Ethanol dehydrated (dried). After evaporation, 11.5 g (74%) of crude are obtained 3-Amino-2- (3-pyridyl) -1-propanol in the form of a viscous, yellow oil.

The IR spectrum is consistent with the assumed structure. To the Confirmation is the compound in pyridine with p-toluenesulfonyl chloride to the O, N-ditosylate derivative, i.e.

2- (3-pyridyl) -3-p-toluene-sulSonamidopropyl-p-toluene-type Sonatia from Bp. 170 to 170,500 implemented.

Example 5 35.2 g (0.23 mol) of the 3-amino-2- (3-pyridyl) -1-propanol from Example 4 are stirred into 335 ml of anhydrous pyridine.

The solution is cooled to 50 and 96.9 are added in portions g (0.509 mol) of p-tosyl chloride, stir it for 2 hours in an ice bath, dilute it with 3 liters. Ice water and cool them at 40C overnight. An oil separates out, which after vigorous rubbing becomes firm. The solid is isolated and washed out with water and dried under reduced pressure. 66.5 g (yield 62.5%) of dark red color are obtained 2- (3 pyridyl) -3- (p-toluenesulfonamido) -propyl-p-toluenesulfonate with a melting point of 150 to 15300.

This sulfonamidosulfonate is then added to a reagent which by incorporating 6.25 g (0.16 mol) of pure potassium metal in 6.5 liters of tert-butanol, which had been refluxed for 90 min. was prepared. The addition takes place at 300C. The solution is boiled for 10 hours with stirring and reflux. then the solution is cooled slightly, 20 g of activated charcoal are added and it is boiled reflux them for an additional hour to effect partial purification. The solution is then filtered and the filtrate is freed from the solvent.

This gives 32 g (77%) of solid crude product, which on 1 kg of silica gel is chromatographed. Elution with 10% acetone in benzene gives 21.2 g of a brown-yellow solid, which is treated again with activated charcoal. Then rub with ether.

The product, i.e. 3- (3-pyridyl) -p-toluenesulfonylazetidine (m.p. 95 to 96.50C) is obtained in a yield of about 37%; IR (Nujol) 1155 and 1340 com 1 (NSo2); NMR (ODO13) Cr 2.5 (s, 3, CH3), 3.95 (m, 5), 7.35 (m, 4), 7.8 (m, 2), 8.4 (m, 2); Mass spectrum m / e (relative intensity) 288 (0.5, M +), 65 (14.6), 106 (22.2), 196 (25.7), 91 (29.9), 105 (100).

Analysis for C15H16N2S0 2: C H N S calc .: 62.47 5.59 9.71 11.12% found: 62.55 5.47 9.70 11.18% Example 6 18.4 g (64 mmol) of that prepared according to Example 5 3- (5-Pyridyl) -p-toluenesulfonylazetidins are dissolved in a solution of 4.7 g (64 mmol) tert-butanol and 1 liter of ethylene glycol dimethyl ether entered. After a short warm-up to 5000 and stirring in an argon atmosphere to complete the solution effect, the temperature is lowered to -600C and a prepared one is added within 2 hours Solution of sodium nphthalinide added, whereby the temperature of the reaction medium holds at -60 to -65 ° C. 60 ml of methanol are then added to the reaction medium and let it stand overnight at room temperature.

The solution obtained is filtered and the filtrate is concentrated under reduced pressure Pressure is strong, the residue is taken up in petroleum ether and filtered again. The clear, discolored petroleum ether filtrate is extracted five times with 20 ml of water each time. The combined aqueous extracts are naphthalene-free down to 20 ml under reduced pressure Concentrated solution of the product. The solution is then azeotroped by distillation distilled with benzene and ethanol to give a benzene solution of the product.

A clear fraction of 1.9 is obtained by distillation in vacuo g (25%) 3- (3-pyridyl) -azetidine of bp 93 to 97 ° C / 0.15 mm; IR (undiluted) 3300 (NH), 1576, 1482, 1428 cm-1; NMR (CDCl3) Cr 2.04 (s, 1, NH)> 3.94 (m, 5H, more aliphatic Ring), 7.18 (dd, J = 4 Hz, 1), 7.71 (dt, J = 2 Hz, 1), 8.5 (m, 2); Mass spectrum m / e (relative intensity) 134 (3.7, M +), 78 (18), 104 (33.3), 105 (100).

The yellow dipicrate is obtained in ethanol and recrystallized from water; Mp. 200 to 201 ° C, analysis for C20H16N8O14: C H N calc .: 40.55 2.72 18.92% found: 40.30 2.82 18.74% Example 7 660 mg (8.83 mmol) of 40% strength by weight aqueous formaldehyde in 9 ml of water and 755 mg (14.5 mmol) of formic acid in 9 ml of water become 920 mg (6.88 mmol) of the 3- (3-pyridyl) -azetidine prepared according to Example 6 are given. The mixture is heated in the steam bath for 2 hours, then cooled to OOC, 1.2 g (14.4 mmol) of sodium bicarbonate are added and the solution is concentrated to 7 ml under reduced pressure a. The solution is then dehydrated (dried) by azeotropic distillation Benzene and ethanol, whereby an anhydrous benzene solution is obtained, the insoluble ones Fractions are filtered off. N-N-ethyl-3- (3-pyridyl) -azetidine is obtained.

Short-path vacuum distillation gives a fraction of 700 mg (58.5%) of a clear, colorless product with a boiling point of 63 to 65 ° C / 0.15 mm; IR- (undiluted) 2780 (NCH3), 1577, 1483, 1429 cm-1 (3-Py); NMR (CDCl3) # 2.37 (s, 3, CH3), OH3)> 3.16 (m, 2 3.70 (m, 3), 7.15 (dd, J = 4 Hz, 1), 7.7 (dt, J = 2 Hz, 1), 8.46 (m, 2); Mass spectrum m / e (relative intensity) 148 (13.0, M +), 104 (34.9), 106 (73.0), 105 (100).

The dipicrate is obtained in ethanol and recrystallized from water; Mp. 191-19200.

Analysis for C21H18N8014C H N calc .: 41.44 2.90 18.50% found: 41.24 2.92 18.58 w Example 8 A mixture of 3.09 g ethoxyamine hydrochloride, 60 ml pyridine and 6 g of ethyl benzoylacetate are heated to 85 ° C. for 18 hours while stirring. Afterward the solvent is evaporated off under reduced pressure and the residue is distributed between methylene dichloride and water. The methylene dichloride phase is then dried and distilled at reduced pressure. This gives 5.5 g (75%) of ethyl 3-phenyl-3-ethoximinopropionate.

A slurry of 512 mg of lithium aluminum hydride is added with 1 g of the ethoximino ester combined in 25 ml of dimethoxyethane. The batch is boiled for 2 hours. under reflux, the mixture is then cooled to OOC, 2.5 ml of saturated sodium chloride solution are added added, the mixture is stirred overnight at room temperature, filtered, and the filtrate is evaporated at reduced pressure, the remaining oil takes up in methylene dichloride and dry the solution over magnesium sulfate.

The solvent is then evaporated off and the crystallized solid residue from benzene / petroleum ether around; this gives 540 mg (74%) 3-phenyl-3-amino-1-propanol from m.p. 72 to 73 ° C, Example 9 Commercially available hydrocinnamic acid is used in their Ethylestei over. The ester is then used in the Bull.Soc.Chim.France, (1951), Pages 895-899, described in the presence of a sodium-potassium alloy with Ethyl formate converted to ethyl a-formylhydrocinnamate.

6 g (29.1 mmol) of the ethyl a-formylhydrocinnamate are in a with Using a magnetic stirrer, a stirred solution of 60 ml of anhydrous pyridine, which 2.49 g (29.8 mmol) of methoxyamine hydrochloride containing, entered. The received The solution is heated to 70 ° C. for 18 hours and then evaporated in vacuo. One distributes the residue between water and methylene dichloride, the organic phase washes with water, dries and evaporates. This gives 6.73 g (99) of ethyl 2-benzyl-3-methoximinopropionate.

1 g (4.25 mmoles) of this intermediate is made into a slurry of 50 ml of anhydrous 1,2-dimethoxyethane, which 482 mg (12.75 mmol) of aluminum hydride contains, registered. The mixture is refluxed for 90 minutes and then cooled OOC off, add 2.5 ml of saturated sodium chloride solution and heat the mixture 1 hour at 600C. The mixture is then filtered, the filtrate is evaporated and dissolved the residue again in methylene dichloride, the solution dried over sodium sulfate, filtered and the filtrate evaporated. This gives 680 mg of crude 2-benzyl-3-amino-1-propanol. A 316 mg sample of the amino alcohol is combined with 173 mg of oxalic acid in 3 ml of absolute Ethanol to the pure, crystalline oxalate of m.p. 149 to 1500C (reported 150 to 15200; CA 41, 13167 g) implemented. The IR, Eern resonance or NMR and Raman analysis are consistent with the right structure.

B e i 5 p i e 1 10 3-Amino-2-phenyl-1-proanol is used analogously to Example 9 by reducing the reaction product of methoxyamine and ethyl 2-formyl-2-phenyl acetate manufactured. The 3-amino-2-phenyl-1-propanol is obtained in the form of a yellow oil.

After conversion into the hydrochloride, the melting point is 119 up to 1200C.

Analysis for CgH14NOCl: C H N Cl calc .: 57.60 7.52 7.46 18.89% found: 57.39 7.50 7.51 18.60%

Claims (22)

Claims 1. A process for the preparation of γ-amino alcohols, da-durchgekenn ze ichnet that one ß-dicarbonyl compound of the general formulas A or B in which R1 is a hydrogen atom or an alkyl, aryl or alkylaryl radical, R2 and R3 each represent a hydrogen atom or an alkyS, aryl, alkylaryl, heteroaromatic or alkylheteroaromatic radical, R4 is a hydrogen atom or an alkyl, aryl or Alt is Raryl radical and R5 is an alkyl radical, reacted with an alkoxyamine to form the xonoalkoximino intermediate and the intermediate product is reduced to the γ-amino alcohol. 2. The method according to claim 1, characterized in that R2 and R3 each represent a hydrogen atom. 3. The method according to claim 1, characterized in that R2 and R3 each represent a heteroaromatic or alkyl heteroaromatic radical. 4. The method according to claim 3, characterized in that R2 is a Pyridyl group and R3 represent a hydrogen atom. 5. The method according to claim 1, characterized in that as Alkoxyamine methoxyamine, ethoxyamine or benzyloxyamine is used. 6. The method according to claim 1, characterized in that the Monoalkoximino intermediate reduced with lithium aluminum hydride. 7 / y-amino alcohols of the general formula below in which R1 is a hydrogen atom or an alkyl, aryl or alkylaryl radical, R2 and R3 each represent a hydrogen atom or an alkyl, aryl-alkylaryl or heteroaromatic radical, at least one of the radicals R2 and R3 being a heteroaromatic radical) and R4 denotes a hydrogen atom or an alkyl, aryl or alkylaryl radical. 8. y-amino alcohols according to claim 7, characterized in that R2 is a phenyl, tolyl, benzyl-> pyridyl or furanyl group. 9. y-amino alcohols according to claim 7, characterized in that R2 represents a pyridyl group and R3 represents a hydrogen atom. 10. y-amino alcohols according to claim 7, characterized in that R2 or R3 represents a heteroaromatic ring which has a nitrogen atom as Has heteroatom. 11. A process for the preparation of azetidine compounds, characterized in that one uses an amino ester of the general formula below in which R1 and R2 each represent a hydrogen atom or an alkyl, aryl, aralkyl-> heteroaromatic or alkylheteroaromatic radical, R3 and R4 each represent a hydrogen atom or an alkyl, aryl, aralkyl-> heteroaromatic or alkylheteroaromatic radical, and R5 represents The alkyl radical is sulfonated to the sulfonamide, the sulfonamide is reduced to the 3-sulfonamido alcohol, the alcohol is sulfonated to the 3-sulfonamidoalkyl sulfonate and the sulfonate is cyclized to the N-sulfonylazetidine compound. 12. The method according to claim 11, characterized in that the N-sulfonylazetidine to form an azetidine compound that is unsubstituted on the nitrogen (N-H-azetidine compound) reduced. 13. The method according to claim 12, characterized in that the azetidine unsubstituted on nitrogen is alkylated to give an N-alkylazetidine derivative. 14. The method according to claim 11, characterized in that at least one of the radicals R1 or R2 is a pyridyl or substituted pyridyl group. 15. The method according to claim 14, characterized in that one the radicals R1 or R2 is a hydrogen atom. 16. The method according to claim 1, characterized in that one has both the sulfonation of the amino ester as well as that of the sulfonamido alcohol with the aid the p-tosyl group. 17. A process for the preparation of azetidine compounds, characterized in that one uses an amino alcohol of the general formula below in which R1 and R2 each represent a hydrogen atom or an alkyl, aryl, aralkyl, heteroaromatic or alkylheteroaromatic radical and R3 and R4 each represent a hydrogen atom or an alkyl, aryl or aralkyl radical, disulfonated to the 3-sulfonamidoalkylsulfonate intermediate and the intermediate product cyclizes to the N-sulfonylazetidine compound. 18. The method according to claim 17, characterized in that the N-sulfonylazetidine compound to form an azetidine compound which is unsubstituted on the nitrogen (N-H-azetidine compound) reduced. 19. The method according to claim 18, characterized in that the azetidine compound unsubstituted on nitrogen is alkylated to form an N-alkylazetidine. 20. The method according to claim 17, characterized in that at least one of the radicals R1 or R2 is a pyridyl or substituted pyridyl group. 21. The method according to claim 20, characterized in that one the radicals R1 or R2 is a hydrogen atom. 22. The method according to claim 21, characterized in that at least one of the radicals R3 and R4 is a hydrogen atom.